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Cystinuria is a genetic disease that can lead to cystine urolith formation. The English bulldog is the dog breed most frequently affected. In this breed, three missense mutations have been suggested to be associated with cystinuria: c.568A>G and c.2086A>G in SLC3A1 and c.649G>A in SLC7A9. In this study, the occurrence of these three mutations in the Danish population of English bulldogs was investigated. Seventy-one English bulldogs were genotyped using TaqMan assays. The dogs' owners were given questionnaires concerning the medical histories of their dogs. Allele frequencies of 0.40, 0.40, and 0.52 were found for the mutant alleles in the three loci: c.568A>G, c.2086A>G, and c.649G>A, respectively. For both mutations in SLC3A1, a statistically significant association was found between cystinuria and homozygosity for the G allele among male, English bulldogs. For the mutation in SLC7A9, there was no statistically significant association between homozygosity for the mutant allele and cystinuria. Due to high allele frequencies, limited genetic diversity, continued uncertainty about the genetic background of cystinuria, and more severe health problems in the breed, selection based on genetic testing for the mutations in SLC3A1 cannot be recommended in the Danish population of English bulldogs. However, results of the genetic test may be used as a guide to recommend prophylactic treatment., (© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Cystinuria is a condition caused by defects in amino acid transport within the kidneys and small intestines. It has been reported in humans, dogs, domestic cats, ferrets, nondomestic canids, and nondomestic felids, including servals ( Leptailurus serval). Genetic mutations have been identified in dogs, humans, and domestic cats. Cystinuria usually follows an autosomal recessive inheritance, although it can be autosomal dominant and sex linked. The primary objective of this study was to screen urine samples dried on filter paper from captive servals in the United States for cystinuria by using the cyanide-nitroprusside screening test. A second objective was to determine whether cystinuria is inheritable in servals. Servals were initially recruited for the study by survey. Owners and institutions interested in participating were sent a second survey and filter paper for collecting urine samples. Samples were collected from 25 servals. One additional serval with confirmed cystine urolithiasis was added for a total sample size of 26 servals. Twenty-seven percent (7/26) were positive, 54% (14/26) were weakly positive, and 19% (5/26) were negative. Sex, reproductive status, and urine collection method had no significant association with test results. This condition is likely underreported in servals and should be ruled out in any serval with nonspecific signs of illness; neurologic signs such as lethargy, ataxia, or seizures; ptyalism; or signs of lower urinary tract disease such as dysuria, hematuria, stranguria, pollakiuria, or urethral obstructions.

Cystinuria is caused by defective proximal renal tubular reabsorption of the amino acids cystine, ornithine, lysine, and arginine (COLA). The low solubility of cystine in mildly acidic urine may lead to the formation of urinary cystine crystals and uroliths. Much progress has been made recently in the diagnosis and understanding of cystinuria in companion animals. In cats, cystinuria affects equally both genders independent of neutering status and, despite being rare, already more cystinuria-causing mutations have been detected in cats compared to dogs. In this study a litter of Siamese-crossbred cats in Germany was assessed clinically for cystinuria and screened for mutations known to cause cystinuria in cats. An adult male castrated cat was presented with cystine crystalluria and calculi-related urinary obstruction and treated with perineal urethrostomy, cystotomy, and medical management. This cat and a neutered male littermate without evidence of urinary tract disease were found to be positive for cystine by urinary nitroprusside test, to have increased urinary COLA values and to be homozygous for the p.Val294Glu mutation in the SLC7A9 gene coding for b 0,+ AT subunit of the b 0,+ renal COLA transporter. Another littermate was non-cystinuric and did not carry this mutation. The same SLC7A9 mutation was previously found in a Maine coon, a Sphinx and a medium-haired cat in North America suggesting a common ancestor and likely first widespread SLC7A9 mutation causing cystinuria in cats. Genetic screening for this mutation may offer a simple and precise mean to diagnose other cats for cystinuria and offer specific management.

Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA) reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 and SLC7A9, which encode the rBAT and bo,+AT subunits of the bo,+ basic amino acid transporter system, respectively. In this study, exons and flanking regions of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA of cats (Felis catus) with COLAuria and cystine calculi. Relative to the Felis catus-6.2 reference genome sequence, DNA sequences from these affected cats revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn) from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu) in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met) from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the bo,+AT protein. A limited population survey supported that the variants found were likely causative. The remaining 2 sequenced domestic short-haired cats had a heterozygous variant at a splice donor site in intron 10 and a homozygous single nucleotide variant at a branchpoint in intron 11 of SLC7A9, respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats.

Background: Cystinuria is an inherited metabolic disease that is relatively common in dogs, but rare in cats and is characterized by defective amino acid reabsorption, leading to cystine urolithiasis., Objectives: The aim of this study was to report on a mutation in a cystinuric cat., Animals: A male domestic shorthair (DSH) cat with cystine calculi, 11 control cats from Wyoming, and 54 DSH and purebred control cats from elsewhere in the United States., Methods: Exons of the SLC3A1 gene were sequenced from genomic DNA of the cystinuric cat and a healthy cat. Genetic screening for the discovered polymorphisms was conducted on all cats., Results: A DSH cat showed stranguria beginning at 2 months of age, and cystine calculi were removed at 4 months of age. The cat was euthanized at 6 months of age because of neurological signs possibly related to arginine deficiency. Twenty-five SLC3A1 polymorphisms were observed in the sequenced cats when compared to the feline reference sequence. The cystinuric cat was homozygous for 5 exonic and 8 noncoding SLC3A1 polymorphisms, and 1 of them was a unique missense mutation (c.1342C>T). This mutation results in a deleterious amino acid substitution (p.Arg448Trp) of a highly conserved arginine residue in the rBAT protein encoded by the SLC3A1 gene. This mutation was found previously in cystinuric human patients, but was not seen in any other tested cats., Conclusions and Clinical Importance: This study is the first report of an SLC3A1 mutation causing cystinuria in a cat, and could be used to characterize other cystinuric cats at the molecular level., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)

Background: Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds., Hypothesis/objectives: To determine urinary cystine concentrations, inheritance, and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds., Animals: Mixed and purebred Labrador Retrievers (n = 6), Australian Cattle Dogs (6), Miniature Pinschers (4), and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs., Methods: Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA., Results: In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed-specific DNA tests were developed, but the prevalence of each mutation remains unknown., Conclusions and Clinical Importance: These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Cystinuria is a genetic disorder in the domestic dog that leads to recurrent urolith formation. The genetic basis of the disorder is best characterized in humans and is caused by mutations in one of the amino acid transporter genes SLC3A1 or SLC7A9, which results in hyperexcretion of cystine and the dibasic amino acids in the urine and subsequent precipitation of cystine due to its low solubility in urine. In this study we describe the cloning of the canine SLC7A9 cDNA and present a thorough mutation analysis of the coding SLC3A1 and SLC7A9 regions in cystinuric dogs of different breeds. Mutation analysis of the two cystinuria disease genes revealed one SLC7A9 mutation (A217T) and two SLC3A1 mutations (I192V and S698G) in French and English Bulldogs that affect nonconserved amino acid residues, arguing against functional impact on the proteins. The absence of deleterious mutations linked to cystinuria in the remainder of our panel of cystinuric dogs is surprising because SLC3A1 or SLC7A9 mutations explain approximately 70% of all human cystinuria cases studied. The present study, along with previous investigations of canine and human cystinuria, implies that regulatory parts of the SLC3A1 and SLC7A9 genes as well as other unknown genes may harbor mutations causing cystinuria.

Cystinuria in Newfoundland dogs is a metabolic disease associated with a nonsense mutation in the exon 2 of the Slc3a1 gene. Similar to type I human cystinuria, heterozygote carriers are not affected by the disease and do not reveal differences in urinary concentration of dibasic amino acids when compared with normal dogs. However, through a recessive mode of inheritance, these dogs are able to transmit the disease to their offspring. Early detection of mutation carriers through cost-effective reliable methods is therefore essential for the implementation of breeding methods aimed at the eradication of the disease. Denaturing high-performance liquid chromatography (DHPLC) is a recently developed technique for rapid and efficient screening of nucleotide polymorphisms in polymerase chain reaction-amplified products. This technique was used for the identification of the C663T Slc3a1 mutation in Portuguese Newfoundland dogs. Polymerase chain reaction products amplified from a region containing the C663T locus were subjected to DHPLC analysis, and results were double checked by DNA sequencing. Results showed the presence of the mutation in 6 of the 22 dogs tested. Urine biochemical parameters correlated well with the number of mutated Slc3a1 copies, and homozygotes for the C663T mutation were the only dogs diagnosed with cystinuria. Sequence analysis confirmed the DHPLC results, demonstrating that the technique could be a reliable alternative to sequencing for the rapid and cost-effective identification of mutations in canine breeds.

A 6-year-old, intact male Chihuahua was presented with stranguria and painful urination of 5 days duration. Cystine crystals were observed in low numbers in unstained urine sediment preparations, and a diagnosis of cystinuria was made. Uroliths were removed surgically from the urethra and the bladder, and mineral analysis indicated the stones were composed of 100% cystine. Cystinuria results from an inherited defect in renal tubular transport of cystine that affects many breeds and has been found as an autosomal recessive trait in Newfoundlands. Accurate identification of cystine crystals in urine is an important means of diagnosing cystinuria.

Objective: To determine taurine status in a large group of Newfoundlands related by environment, diet, or breeding to a dog with dilated cardiomyopathy and taurine deficiency., Design: Prospective study., Animals: 19 privately owned Newfoundlands between 5 months and 11.5 years old that had been fed commercial dry diets meeting established nutrient recommendations., Procedure: Diet histories were obtained, and blood, plasma, and urine taurine concentrations and plasma methionine and cysteine concentrations were measured. In 8 dogs, taurine concentrations were measured before and after supplementation with methionine for 30 days. Ophthalmic examinations were performed in 16 dogs; echocardiography was performed in 6 dogs that were taurine deficient., Results: Plasma taurine concentrations ranged from 3 to 228 nmol/mL. Twelve dogs had concentrations < 40 nmol/mL and were considered taurine deficient. For dogs with plasma concentrations < 40 nmol/mL, there was a significant linear correlation between plasma and blood taurine concentrations. For dogs with plasma concentrations > 40 nmol/mL, blood taurine concentrations did not vary substantially. Taurine-deficient dogs had been fed lamb meal and rice diets. Retinal degeneration, dilated cardiomyopathy, and cystinuria were not found in any dog examined for these conditions. The taurine deficiency was reversed by a change in diet or methionine supplementation., Conclusions and Clinical Relevance: Results indicate a high prevalence of taurine deficiency among an environmentally and genetically related cohort of Newfoundlands fed apparently complete and balanced diets. Blood taurine concentrations indicative of taurine deficiency in Newfoundlands may be substantially less than concentrations indicative of a deficiency in cats.

The purpose of this study was to summarize 14 years of clinical experience with medical treatment of 88 cystinuric dogs. Of special interest was evaluation of recurrence rate of cystine uroliths and adverse effects during long-term tiopronin treatment. Twenty-six different breeds were recognized, and the most common breeds were Dachshunds, Tibetan Spaniels, and Basset Hounds. In 76 of 88 treated dogs (86%), re-formation of cystine uroliths was prevented. Recurrence rate of cystine uroliths changed from 7 months before to 18 months during tiopronin treatment. On 28 occasions, bladder stones were found, and in about 60% of the dogs, the uroliths dissolved. Quantitative measurement of the urinary excretion of cystine showed a significantly (P < .03) higher excretion of cystine in dogs with recurrent urolith formation than in dogs with only 1 urolith episode. Another finding was a significant (P = .02) decrease in urinary cystine excretion in older (>5 years) than in younger (<5 years) dogs. Adverse effects were found in 11 dogs, and the most severe signs were aggressiveness and myopathy. All signs disappeared when tiopronin treatment was stopped. In conclusion, this study emphasizes the importance of an individual strategy for lifelong treatment of cystinuria. In addition to increasing water intake, chemical modification of the cysteine molecule into a more soluble form by means of tiopronin is useful. In dogs with re-formed cystine uroliths, dissolution may be induced by increasing the tiopronin dosage to 40 mg/kg body weight per day. In dogs with a low urolith recurrence rate and low urinary cystine excretion, the tiopronin dosage may be decreased or treatment discontinued.

Five client owned dogs with cystinuria were diagnosed with carnitine and taurine deficiency while participating in a clinical trial that used dietary management of their urolithiasis. Stored 24-hour urine samples collected from the cystinuric dogs before enrollment in the clinical diet trial were quantitatively evaluated for carnitine and taurine. These results were compared to those obtained from 18 healthy Beagles. Both groups of dogs were fed the same maintenance diet for a minimum of 2 weeks before 24-hour urine collection. The protocol used for 24-hour urine collections was the same for cystinuric dogs and healthy Beagles except that cystinuric dogs were catheterized at baseline, 8 hours, 12 hours, and at the end of the collection, whereas Beagles were catheterized at baseline, 8 hours, and at the end of the collection. Three of 5 dogs with cystinuria had increased renal excretion of carnitine. None of the cystinuric dogs had increased renal excretion of taurine, but cystinuric dogs excreted significantly less (P < .05) taurine in their urine than the healthy Beagles. Carnitinuria has not been recognized previously in either humans or dogs with cystinuria, and it may be 1 risk factor for developing carnitine deficiency. Cystinuric dogs in this study were not taurinuric; however, cystine is a precursor amino acid for taurine synthesis. Therefore, cystinuria may be 1 risk factor for developing taurine deficiency in dogs. We suggest that dogs with cystinuria be monitored for carnitine and taurine deficiency or supplemented with carnitine and taurine.

Cystinuria is an inherited renal and intestinal disease characterized by defective amino acid reabsorption and cystine urolithiasis. Different forms of the disease, designated type I and non-type I in cystinuric humans, can be distinguished clinically and biochemically, and have been associated with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Type I cystinuria is the most common form and is inherited as an autosomal recessive trait in humans. Cystinuria has been recognized in more than 60 breeds of dogs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Here we report the cloning and sequencing of the canine SLC3A1 cDNA and gene, and the identification of a nonsense mutation in exon 2 of the gene in cystinuric Newfoundland dogs. A mutation-specific test was developed for the diagnosis and control of cystinuria in Newfoundland dogs. In cystinuric dogs of six other breeds, either heterozygosity at the SLC3A1 locus or lack of mutations in the coding region of the SLC3A1 gene were observed, indicating that cystinuria is genetically heterogeneous in dogs, as it is in humans. The canine homologue of human type I cystinuria provides the opportunity to use a large animal model to investigate molecular approaches for the treatment of cystinuria and other renal tubular diseases.

The careful analysis of cystine calculi may be important to detect the presence of other urinary alterations (such as hyperuricosuria, hypercalciuria, hyperoxaluria or bacterial infections) that coexist with cystinuria in many patients. For this reason, in the present study, 14 human and 17 canine cystine uroliths have been studied by infrared spectroscopy (IR), scanning electron microscopy (SEM), and energy dispersive X-ray analysis (EDX). According to the infrared analysis, most of the human and canine stones were composed of nearly pure cystine. However, in these calculi of apparently pure cystine, the study by SEM and EDX showed in many cases the presence of small amounts of calcium apatite. The infrared study of several samples heated at 750 degrees C confirmed the presence of phosphate, when it was difficult to detect this component in the spectra of the original samples owing to band overlapping. Other components detected in varying proportions in cystine calculi were magnesium ammonium phosphate hexahydrate (struvite), calcium hydrogen phosphate dihydrate (brushite), calcium oxalate (mono and/or dihydrate) and, in one case, a drug (oxolinic acid).

Cystine uroliths are a sequela to cystinuria, an inherited renal tubular defect in reabsorption of cystine and some other amino acids. At the Minnesota Urolith Center, 67 breeds of dogs were identified, including English Bulldogs, Dachshunds, Mastiffs, and Newfoundlands. In some dogs, the severity of cystinuria may decline with advancing age. Current recommendations for dissolution of cystine uroliths include various combinations of diet modification, diuresis administration of 2-MPG, and alkalinization of urine.

Objective: To describe clinical features, characterize metabolic renal abnormalities, and evaluate mode of inheritance of cystinuria in Newfoundlands., Design: Prospective study., Animals: Two families of Newfoundlands including 11 dogs with dysuria, stranguria, or obstruction attributable to cystine calculi., Procedure: Urinalysis and nitroprusside spot tests were performed to evaluate cystinuria in the affected dogs. All calculi were analyzed by crystallography. Amino acid concentrations in urine and plasma of affected dogs were compared with those in clinically normal related dogs. Renal fractional excretion and reabsorption of amino acids were determined in 5 affected Newfoundlands., Results: Nine dogs had pure cystine calculi in the bladder, and 4 of these had renal cystine calculi. Affected dogs persistently excreted excessive amounts of cystine (> 500 nmol/mg of creatinine; reference = 54 +/- 38 nmol/mg of creatinine) and had typical cystine crystals in acidic urine. Urinary excretion of ornithine, lysine, and arginine was also high. Dogs with cystinuria had complete lack of reabsorption and active secretion of cystine, and reabsorption of lysine, ornithine, and arginine was moderately impaired. Although clinical signs of urinary obstruction were observed only in males, cystinuric male and female offspring were produced from noncystinuric parents, consistent with an autosomal recessive mode of inheritance. Obligate heterozygotes did not have clinical signs, and had normal urinary cystine content and renal amino acid reabsorption., Clinical Implications: Because detection of carriers by routine urinalysis is currently not possible, Newfoundlands with cystinuria and their parents and offspring should be excluded from breeding.

A clinical study covering 1 to 6 years was undertaken during which 25 cystinuric dogs were orally treated with 2-mercaptopropionylglycine (2-MPG). The drug was effective at dissolving uroliths at a dose of approximately 40 mg kg-1 body weight. In 15 dogs with bladder uroliths, complete urolith dissolution was achieved on 9/17 occasions (53%). When 2-MPG was administered prophylactically at 30 mg/kg body weight, uroliths did not reform in 14 dogs (56%). In four dogs, uroliths re-formed during treatment, but dissolved when the dose of 2-MPG was raised to 40 mg kg-1 body weight. Six dogs were surgically treated, and in two of these animals the uroliths were found to consist of magnesium ammonium phosphate. Euthanasia was performed on six dogs during the study; three because of recurrent uroliths with urethral obstruction, and three because of aging. In one dog, uroliths were present in the bladder throughout the study. The purpose of the study was to propose a new strategy for individual treatment of cystinuric dogs. This was accomplished by measuring the urinary free cystine concentration and the mixed cysteine-2-MPG disulphide in a subgroup of 15 of the 25 dogs. To evaluate cystine excretion, morning samples of urine were used, and the cystine concentration was related to the creatinine concentration. For dose adjustment it was difficult to evaluate the effect of 2-MPG on urinary cystine excretion, especially when cystine uroliths were present. However, this variable was studied in order to identify dogs with a strong tendency for urolith formation during 2-MPG treatment. In some cases, urinary cystine excretion returned to normal with time, and in three dogs, 2-MPG treatment could be stopped after 1.5 to 3.5 years. In spite of no further treatment, urinary cystine was almost undetectable up to 2 years later, and the dogs did not develop any new uroliths. It was concluded that 2-MPG is a satisfactory alternative treatment for cystinuric dogs. It has a good prophylactic effect, shown as a change in the rate of urolith formation from on average 6 months before to 17 months during 2-MPT treatment. The drug was shown to have few side effects, and the dog owner drug compliance can be followed by measurement of the mixed 2-MPG-cysteine disulphide.

The 24-h urine excretion of 20 amino acids was investigated in 24 cystinuric and 15 normal dogs. The diagnosis of cystinuria was based on infrared spectroscopy of removed uroliths, which in all cases were composed of pure cystine. Seven of 24 cystinuric dogs showed normal cystine excretion compared to normal dogs, and four of 24 dogs showed normal total amino acid excretion. In contrast to earlier investigations, almost half of the cystinuric dogs (46%) showed elevated excretion of five or more amino acids. Isolated cystinuria, or isolated dibasic amino aciduria was not found. Compared to normal dogs, the cystinuric dogs showed a significantly (P < 0.05) increased excretion of cystine, arginine, lysine, cystathionine, glutamic acid, threonine and glutamine. There was a significant correlation (P < 0.05) between the urinary excretion of cystine and 10 other amino acids, with the highest correlation found (P < 0.001) for arginine, lysine, cystathionine, ornithine and 1-methyl-histidine. Three patterns of amino acid excretion could be identified: (1) increased excretion and a significant correlation with cystine for the three dibasic amino acids (lysine, arginine and ornithine), compatible with a common reabsorption mechanism as shown in man. This pattern was also found for cystathionine and glutamic acid, which might indicate a relation in metabolism or transport; (2) increased excretion but no correlation with cystine for glutamine, threonine and citrulline; (3) good correlation with cystine, but no increased excretion for 1-methyl-histidine, phenylalanine, 3-methyl-histidine, leucine and alanine. The great variation in urinary cystine excretion suggests that factors other than the excretion of cystine must be considered as causes of cystine urolith formation. For example, cystinuric dogs were found to have lower diuresis than normal dogs and produced urine with higher cystine concentration thereby increasing the risk of cystine urolith formation.

Urinary excretion of metals during treatment with 2-mercaptopropionylglycine (2-MPG) was studied in 11 normal and 20 cystinuric male dogs. The results were compared with those obtained during D-penicillamine treatment. Twenty-four-h urine and morning samples of urine were taken for determination of 13 metals before and during treatment. After single intravenous and oral D-penicillamine treatment of the normal dogs, significant increases were found in the 24-h urinary excretion of Ca, Cu and Zn. Oral intake of D-penicillamine increased the excretion of Co, Cr, Fe and Mg as well. No effect on renal metal excretion was observed after single intravenous and up to 2 months of daily oral treatment with 2-MPG. In 14 cystinuric dogs no effect was found after single intravenous and oral administrations of 2-MPG. However, after oral treatment of six cystinuric dogs with 2-MPG for 2-4 months, significantly increased excretions of Ca and Mg were found. Fourteen of the cystinuric dogs were also investigated after 2-6 years of continuous 2-MPG treatment, and after this period no significant elevation in the urinary excretion of metals was found. The present study shows that in contrast to D-penicillamine, 2-MPG does not increase the urinary excretion of metals to any appreciable extent. Observed increases in the excretion of Ca and Mg seemed to be a temporary effect only.

The pharmacokinetic disposition of 2-mercaptopropionylglycine (2-MPG) given as a single intravenous injection and/or as a single oral dose was studied in 9 normal and 13 cystinuric dogs. After intravenous injection of approximately 10 or 20 mg/kg body weight the pharmacokinetics were best described by a three-exponential function. The first phase involved a distribution process apparently including establishment of drug-plasma protein and drug-tissue binding. The second phase involved rapid renal elimination and 60% of the drug was excreted within 3 h of administration. There was also a slow terminal third phase with a long half-life after both intravenous (t1/2 = 23 h) and oral (t1/2 = 22 h) administration. No dose dependency was observed. A deep pool of reversibly tissue-bound 2-MPG was indicated by a Vss of 3.3 +/- 0.9 l/kg body weight and the long terminal elimination phase. Total clearance was estimated as 4.1 +/- 0.9 ml/min/kg body weight. 2-MPG was eliminated mainly by renal excretion, but there was a difference in recovery of dose between normal and cystinuric dogs. During the first 24 h after intravenous and oral administration, 69% and 54%, respectively, of the drug was recovered in the urine of normal dogs. The corresponding figures in cystinuric dogs were 44% and 29%, respectively. The absolute bioavailability (FAUC) was 88 +/- 20% in normal dogs.

A 10-month-old male Siamese cat with dysuria was determined to have cystine crystalluria. Many small calculi composed entirely of cystine were found in the urinary bladder. Measurement of serum and urine amino acids and calculation of fractional reabsorption of amino acids indicated reabsorption defects for cystine, ornithine, lysine, and arginine. Urinary acidification, fractional reabsorption of glucose, and fractional reabsorption of electrolytes were normal. Diagnoses of cystinuria and cystine urolithiasis were made on the basis of low fractional reabsorption of cystine and dibasic amino acids and the detection of cystine calculi in the urinary bladder.

This article contains an analysis of data compiled from 813 specimens of canine uroliths submitted to the Urinary Stone Analysis Laboratory at University of California School of Veterinary Medicine.

In a pharmacokinetic and tolerance study, 2 healthy Beagles were given 13.2 to 39.5 mg of 2-mercaptopropionylglycine (2-MPG)/kg of body weight orally once daily in increasing doses for 3 weeks. A third dog was given 10 mg of 2-MPG/kg of body weight, IV. The drug was well tolerated. After these initial studies, 15 cystinuric dogs were treated with 2-MPG orally once daily for 5 to 45 months and with sodium bicarbonate for urine alkalinization and fluid diuresis. Pharmacokinetic studies were done in 7 dogs on the third day of oral treatment with 2-MPG. After oral administration of 15.6 to 31.3 of 2-MPG/kg of body weight, maximal serum/plasma concentrations were from 28.6 to 76.3/mumol/L after 1 to 3 hours in 6 cystinuric dogs. The mean urinary excretion was 22% (range, 0.3 to 58.9%) of the dose. Ten of 15 cystinuric dogs had no re-formation of uroliths. Of 4 dogs with uroliths at the beginning of treatment, 3 had total urolith dissolution on continuous treatment. During treatment, further growth of the uroliths was inhibited in one dog, and in another dog with re-formed uroliths, they dissolved. We concluded that 2-MPG is well tolerated and promising for treatment of cystinuric dogs, but the pharmacokinetic studies should be expanded to include different dosage regimens, and results of long-term treatment should be evaluated. Our recommendations for treatment of dogs with cystine uroliths include surgical intervention if the dog has urethral obstruction or has dysuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Cystine uroliths form as a result of a complex metabolic disturbance in amino acid metabolism and transport. The inheritance of this disease is obscure because it does not follow a standard mendelian pattern. Uroliths are a vexing clinical problem because the recurrence rate is high. Accurate diagnosis of uroliths requires use of crystallographic methods. The renal defect leading to excessive excretion of cystine is variable. The only effective method of prevention of recurrence is use of D-penicillamine, which is poorly tolerated by some dogs.

A renal calculus composed principally of the amino acid, cystine, was found in an 8-year-old male maned wolf (Chrysocyon brachyurus). Cystine crystals were found in the urine sediment. The renal clearance of 10 amino acids was abnormal, whereas reabsorption of others was normal. The renal clearance of cystine, lysine, ornithine, and arginine exceeded the filtered load. The renal tubular handling of glucose, phosphate, sodium, potassium, and uric acid was identical to that for the clinically normal dog. These findings indicated an isolated renal tubular defect for cystine and other amino acids.

Of 42 maned wolves in zoos or live-trapped in Brazil, 34 had excessive cystine in their urine. Renal clearance studies of five of the affected wolves revealed a variable defect for the reabsorption of cystine and dibasic amino acids. The renal tubular handling of other solutes including glucose, phosphate, sodium, potassium, and uric acid was considered normal. Urinary calculi composed of cystine were found in four wolves and proved fatal in three of them. With the exception of the high incidence in this species, this hereditary disease resembles the disorder described in dogs and humans.

A study was performed to compare qualitative test results of canine uroliths with quantitative test results. Qualitative test results were in agreement with quantitative test results in only 96 of 223 specimens (43 per cent). Lack of agreement was caused by false-negative qualitative test results (85 of 223), false-positive qualitative test results (15 of 233), and a combination of false-negative and false-positive qualitative test results (27 of 233). This study indicates that the veterinary profession should abandon exclusive use of qualitative chemical test kits for uroliths.

Crystalluria results from oversaturation of urine with crystallogenic substance. However, oversaturation may occur as a result of in vitro as well as in vivo events. The microscopic appearance of crystals only represents a tentative identification of their composition because variable conditions associated with their formation, growth, and dissolution may alter their appearance. Definitive identification is dependent on physical methods such as optical crystallography, x-ray diffraction, and electron microscopic analysis.